Efficacy of adjunctive lumateperone 42 mg treatment across patient-reported depression symptoms in major depressive disorder
W.R. Earley1, S. Durgam2, R. Migliore3, Y. Mo4, H. Lakkis5, S.G. Kornstein6, M. Fava7
1Intra-Cellular Therapies, a Johnson & Johnson Company, Senior Vice President, Head of Clinical Development, Bedminster, United States, 2Intra-Cellular Therapies, a Johnson & Johnson Company, Chief Medical Officer, Executive Vice President, Bedminster, United States, 3Intra-Cellular Therapies, a Johnson & Johnson Company, Associate Vice President, Clinical Development, Bedminster, United States, 4Intra-Cellular Therapies, a Johnson & Johnson Company, Biostatistics, Bedminster, United States, 5Intra-Cellular Therapies, a Johnson & Johnson Company, VP, Head of Biometric, Bedminster, United States, 6Virginia Commonwealth University School of Medicine, Department of Psychiatry, Richmond, United States, 7Massachusetts General Hospital and Harvard Medical School, Head of the Department of Psychiatry, Boston, United States
Background: Patient-reported outcomes are increasingly used as endpoints in clinical trials, as they offer a unique perspective about symptoms and ensure comprehensive treatment assessment. Because patients with major depressive disorder (MDD) often experience persistent depression symptoms, a treatment for MDD that improves patient-reported symptoms would be beneficial.
Lumateperone is a mechanistically novel FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder, and as adjunctive therapy for MDD. In a previous Phase 3, randomized, double-blind, placebo-controlled trial (Study 502, NCT05061706), adjunctive lumateperone 42 mg met the primary endpoint, significantly improving Montgomery-Asberg Depression Rating Scale (MADRS) Total score vs adjunctive placebo, and was generally well tolerated in patients with MDD with inadequate antidepressant therapy (ADT) response.
Lumateperone is a mechanistically novel FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder, and as adjunctive therapy for MDD. In a previous Phase 3, randomized, double-blind, placebo-controlled trial (Study 502, NCT05061706), adjunctive lumateperone 42 mg met the primary endpoint, significantly improving Montgomery-Asberg Depression Rating Scale (MADRS) Total score vs adjunctive placebo, and was generally well tolerated in patients with MDD with inadequate antidepressant therapy (ADT) response.
Aims & Objectives: This analysis of Study 502 evaluated the efficacy of adjunctive lumateperone 42 mg across patient-reported depression symptoms measured by symptom domains of the Quick Inventory of Depressive Symptomatology-Self Report-16 item (QIDS-SR-16) score.
Method: Eligible adults (18-65y) met DSM-5 criteria for MDD with inadequate response to 1-2 ADTs in the current depressive episode (<50% improvement on the Antidepressant Treatment Response Questionnaire) and had MADRS Total score ≥24, Clinical Global Impression-Severity score ≥4, and QIDS-SR-16 score ≥14. Patients were randomized (1:1) to receive 6-week lumateperone 42 mg or placebo adjunctive to ADT. A prespecified analysis measured change from baseline to end of treatment (EOT) in QIDS-SR-16 Total score using an analysis of covariance (ANCOVA) in the intent-to-treat (ITT) population. Post hoc analyses measured changes using an ANCOVA in the ITT population in the 9 symptom domains of the QIDS-SR-16 score: sleep disturbance (highest score of items 1-4), sad mood, appetite/weight change (highest score of items 6-9), concentration, self-criticism, suicidal ideation, interest, energy/fatigue, and psychomotor agitation/retardation (highest score of items 15-16).
Results: All 480 treated patients were included in the ITT population (lumateperone + ADT, n=242; placebo + ADT, n=238), and 429 (89.4%) completed treatment. Lumateperone + ADT significantly improved QIDS-SR-16 Total score vs placebo + ADT from baseline to EOT (least squares mean difference vs placebo [LSMD], −2.2; effect size [ES], −0.45; P<.0001).
The most prominent QIDS-SR-16 symptom domains at baseline in the lumateperone + ADT group were sleep disturbance (mean: lumateperone + ADT, 2.7; placebo + ADT, 2.7), sad mood (lumateperone + ADT, 2.6; placebo + ADT, 2.7) and concentration (lumateperone + ADT, 2.3; placebo + ADT, 2.3).
From baseline to EOT, 6 of 9 QIDS-SR-16 symptom domains significantly improved with lumateperone + ADT vs placebo + ADT: sleep disturbance (LSMD, −0.61; ES, −0.65; P<.0001); sad mood (LSMD, −0.35; ES, −0.41; P<.0001); appetite/weight change (LSMD, −0.11; ES, −0.12; P=.179); concentration (LSMD, −0.20; ES, −0.25; P<.01); self-criticism (LSMD, −0.33; ES, −0.37; P<.0001); suicidal ideation (LSMD, −0.04; ES, −0.12; P=.188); interest (LSMD, −0.29; ES, −0.32; P<.001); energy/fatigue (LSMD, −0.21; ES, −0.26; P<.01); and psychomotor agitation/retardation (LSMD, −0.12; ES, −0.17; P=.065).
The most prominent QIDS-SR-16 symptom domains at baseline in the lumateperone + ADT group were sleep disturbance (mean: lumateperone + ADT, 2.7; placebo + ADT, 2.7), sad mood (lumateperone + ADT, 2.6; placebo + ADT, 2.7) and concentration (lumateperone + ADT, 2.3; placebo + ADT, 2.3).
From baseline to EOT, 6 of 9 QIDS-SR-16 symptom domains significantly improved with lumateperone + ADT vs placebo + ADT: sleep disturbance (LSMD, −0.61; ES, −0.65; P<.0001); sad mood (LSMD, −0.35; ES, −0.41; P<.0001); appetite/weight change (LSMD, −0.11; ES, −0.12; P=.179); concentration (LSMD, −0.20; ES, −0.25; P<.01); self-criticism (LSMD, −0.33; ES, −0.37; P<.0001); suicidal ideation (LSMD, −0.04; ES, −0.12; P=.188); interest (LSMD, −0.29; ES, −0.32; P<.001); energy/fatigue (LSMD, −0.21; ES, −0.26; P<.01); and psychomotor agitation/retardation (LSMD, −0.12; ES, −0.17; P=.065).
Discussion & Conclusions: Lumateperone 42 mg + ADT significantly improved a broad range of patient-reported depression symptoms vs placebo + ADT in patients with MDD with inadequate ADT response.
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